Polymorphic forms of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl) piperazine hydrochloride

ABSTRACT

The invention relates to new crystalline modifications of the hydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine, crystalline modification of the dihydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride which are suitable in particular for the preparation of solid medicaments for the treatment or prevention of depressive disorders, anxiety disorders, bipolar disorders, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleeping disorders, psychiatric disorders, cerebral infarct, tension, for the therapy of side-effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and undesired puerperal lactation.

RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 13/658,088, filed on Oct. 23, 2012; which is acontinuation of U.S. patent application Ser. No. 13/085,117, filed Apr.12, 2011, now U.S. Pat. No. 8,318,744, issued Nov. 27, 2012; which is acontinuation application of U.S. patent application Ser. No. 12/566,835,filed Sep. 25, 2009, now U.S. Pat. No. 7,981,894, issued Jul. 19, 2011;which is a divisional application of U.S. patent application Ser. No.12/110,704, filed Apr. 28, 2008, now U.S. Pat. No. 7,834,020, issuedNov. 16, 2010; which is a divisional application of U.S. patentapplication Ser. No. 10/481,270, filed Dec. 19, 2003, now U.S. Pat. No.7,381,726, issued Jun. 3, 2008; which is a national phase application ofInternational Application No. PCT/EP2002/006153, filed Jun. 5, 2002;which claims priority to European Patent Application No. 01113647.0,filed Jun. 19, 2001. The entire contents of each of the foregoingapplications and patents are hereby incorporated in their entirety byreference.

FIELD OF THE INVENTION

The present invention relates to novel compounds, to processes forpreparing them and to their use in treating medical disorders.

BACKGROUND OF THE INVENTION

1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine,its physiologically acceptable salts thereof (U.S. Pat. No. 5,532,241,column 7, lines 30 to 58), a process (U.S. Pat. No. 5,532,241, Example4) by which it/they can be prepared and their use in treating certainmedical disorders are known from U.S. Pat. No. 5,532,241 and WO00/72832.

Example 4 of U.S. Pat. No. 5,532,241 describes the preparation of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride by reacting1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carboxybenzofuran-5-yl)piperazine atfirst with 2-chloro-1-methylpyridinium methanesulfonate inN-methylpyrrolidine and then with dried NH₃. Customary working up givesthe free base1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carboxybenzofuran-5-yl)piperazine.700 mg of the base are dissolved in 30 ml 2-propanol under heating andthen treated with 0.1 n 2-propanolic HCL-solution (Merck-Art. No.1.00326) until precipitation of hydrochloride is complete. Theprecipitate was filtered off and washed with diethylether and dried atroom temperature to yield1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride having a melting point of 269-272° C. There is no clearteaching elsewhere in the document of any alternative route ormodification to the process which would generate new crystalmodifications of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride or new solvates or hydrates of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in different crystal modifications.

Former1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride having a melting point of 269-272° C. was a mixture ofamorphous1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, crystallized1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride and the free base1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine.

Certain crystalline, i.e. morphological forms of pharmaceuticalcompounds may be of interest to those involved in the development of asuitable dosage form because if the morphological form is not heldconstant during clinical and stability studies, the exact dosage used ormeasured may not be comparable from one lot to the next. Once apharmaceutical compound is produced for use, it is important torecognize the morphological form delivered in each dosage form to assurethat the production process use the same form and that the same amountof drug is included in each dosage. Therefore, it is imperative toassure that either a single morphological form or some known combinationof morphological forms is present. In addition, certain morphologicalforms may exhibit enhanced thermodynamic stability and may be moresuitable than other morphological forms for inclusion in pharmaceuticalformulations.

SUMMARY OF THE INVENTION

Methods for preparing pure crystals of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride have now been found. Furthermore, surprisingly,1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinedihydrochloride, six (five+dihydrochloride XIII) new forms of1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride, three new forms of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrate, six new forms of solvates of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride and pure amorphous1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride have been found as have processes for their preparation.These forms are hereinafter referred to as I, II, III, IV, V, VI, VII,VIII, IX, X, XI, XIII, XIV, XV and XVI respectively. Throughout thespecification, the term “Form” is generally used as a synonym for theterm “modification” or “crystalline modification.”

Accordingly, the present invention provides solvates of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in crystalline modifications and their use for thetreatment and prevention of depressive disorders, anxiety disorders,bipolar disorders, mania, dementia, substance-related disorders, sexualdysfunctions, eating disorders, obesity, fibromyalgia, sleepingdisorders, psychiatric disorders, cerebral infarct, tension, for thetherapy of side-effects in the treatment of hypertension, cerebraldisorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea,premenstrual syndrome and undesired puerperal lactation.

The present invention furthermore provides1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrates in crystalline modifications and their use forthe treatment and prevention of depressive disorders, anxiety disorders,bipolar disorders, mania, dementia, substance-related disorders, sexualdysfunctions, eating disorders, obesity, fibromyalgia, sleepingdisorders, psychiatric disorders, cerebral infarct, tension, for thetherapy of side-effects in the treatment of hypertension, cerebraldisorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea,premenstrual syndrome and undesired puerperal lactation.

The present invention also provides1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride anhydrates in crystalline modifications and their use forthe treatment and prevention of depressive disorders, anxiety disorders,bipolar disorders, mania, dementia, substance-related disorders, sexualdysfunctions, eating disorders, obesity, fibromyalgia, sleepingdisorders, psychiatric disorders, cerebral infarct, tension, for thetherapy of side-effects in the treatment of hypertension, cerebraldisorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea,premenstrual syndrome and undesired puerperal lactation.

The present invention relates additionally to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinedihydrochloride in its crystalline modification and its use for thetreatment and prevention of depressive disorders, anxiety disorders,bipolar disorders, mania, dementia, substance-related disorders, sexualdysfunctions, eating disorders, obesity, fibromyalgia, sleepingdisorders, psychiatric disorders, cerebral infarct, tension, for thetherapy of side-effects in the treatment of hypertension, cerebraldisorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea,premenstrual syndrome and undesired puerperal lactation.

The present invention relates additionally to pure amorphous1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride and its use for the treatment and prevention of depressivedisorders, anxiety disorders, bipolar disorders, mania, dementia,substance-related disorders, sexual dysfunctions, eating disorders,obesity, fibromyalgia, sleeping disorders, psychiatric disorders,cerebral infarct, tension, for the therapy of side-effects in thetreatment of hypertension, cerebral disorders, chronic pain, acromegaly,hypogonadism, secondary amenorrhea, premenstrual syndrome and undesiredpuerperal lactation.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an IR absorption spectra of Form I

FIG. 2 is an IR absorption spectra of Form II

FIG. 3 is an IR absorption spectra of Form XV

FIG. 4 is an IR absorption spectra of Form XI

FIG. 5 is an IR absorption spectra of Form XIV

FIG. 6 is an IR absorption spectra of Form V

FIG. 7 is an IR absorption spectra of Form VI

FIG. 8 is an IR absorption spectra of Form VIII

FIG. 9 is an IR absorption spectra of Form IV

FIG. 10 is an IR absorption spectra of Form III

FIG. 11 is an IR absorption spectra of Form VII

FIG. 12 is an x-ray diffractogram of Form I

FIG. 13 is an x-ray diffractogram of Form II

FIG. 14 is an x-ray diffractogram of Form XV

FIG. 15 is an x-ray diffractogram of Form X

FIG. 16 is an x-ray diffractogram of Form XI

FIG. 17 is an x-ray diffractogram of Form XIV

FIG. 18 is an x-ray diffractogram of Form V

FIG. 19 is an x-ray diffractogram of Form VI

FIG. 20 is an x-ray diffractogram of Form VIII

FIG. 21 is an x-ray diffractogram of Form IV

FIG. 22 is an x-ray diffractogram of Form III

FIG. 23 is an x-ray diffractogram of Form VII

FIG. 24 is an x-ray diffractogram of Form IX

FIG. 25 is an x-ray diffractogram of Form XIII

FIG. 26 is an x-ray diffractogram of Form XVI

FIG. 27 is an energy/temperature diagram of Forms III, IV and VII

FIG. 28 is a diagram of thermal analysis of Form I

FIG. 29 is a diagram of thermal analysis of Form II

FIG. 30 is a diagram of thermal analysis of Form III

FIG. 31 is a diagram of thermal analysis of Form IV

FIG. 32 is a diagram of thermal analysis of Form V

FIG. 33 is a diagram of thermal analysis of Form VI

FIG. 34 is a diagram of thermal analysis of Form VII

FIG. 35 is a diagram of thermal analysis of Form VIII

FIG. 36 is a diagram of thermal analysis of Form IX

FIG. 37 is a diagram of thermal analysis of Form XI

FIG. 38 is a diagram of thermal analysis of Form XIV

FIG. 39 is a diagram of thermal analysis of Form XV

FIG. 40 is a Raman spectra of Form XIV

FIG. 41 is a Raman spectra of Form XI

FIG. 42 is a Raman spectra of Form V

FIG. 43 is a Raman spectra of Form IV

FIG. 44 is a Raman spectra of Form III

FIG. 45 is a Raman spectra of Form II

FIG. 46 is a Raman spectra of Form I

DETAILED DESCRIPTION OF THE INVENTION

It has been found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is able to form solvates in crystalline modifications.Examples of such solvates include solvates from water, solvates fromalcohols such as methanol, ethanol, propan-1-ol or propan-2-ol; solvatesfrom organic esters such as ethyl acetate; solvates from nitriles suchas acetonitrile; solvates from ketones such as acetone and butanone;solvates from ethers such as tetrahydrofuran and solvates fromchlorinated hydrocarbons such as chloroform and solvates of hydrocarbonssuch as n-heptane or toluene. Preferred solvates are formed with polarsolvents, preferably water, alcohols, organic esters, nitriles, ketonesand ethers.

Preferably,1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride forms solvates with acetone, tetrahydrofuran, methanol,ethyl acetate or n-heptane in crystalline modifications that means thebound solvent together with1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride build the crystal structure. The molar ratio of thesolvent to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride could vary as known to skilled persons in the art.Preferably, the molar ratio is between 0.25:1 to 2.5:1, more preferablybetween 0.5:1 to 1:1, most preferably 1:1. (n-heptan solvate 1/15:1)

It should be understood that the present solvates of the invention maycontain unbound water that is to say water which is other than water ofcrystallization.

Preferred forms of solvates of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride include:

-   -   a)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with acetone in Form I; (as hereinafter        defined),    -   b)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran in Form II; (as        hereinafter defined),    -   c)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran in Form XV; (as        hereinafter defined),    -   d)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran in Form X; (as        hereinafter defined),    -   e)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with methanol in Form XI; (as hereinafter        defined), and    -   f)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with n-heptane in Form XIV; (as        hereinafter defined).

Generally, the specific crystalline forms of the present invention havecertain advantages over the product obtained according to U.S. Pat. No.5,532,241.

Among others, the most important advantages are:

-   -   reduced hygroscopicity,    -   better compressibility during the tablating process,    -   prolonged shelf life,    -   better thermodynamic stability, i.e. stability against heat and        humidity,    -   better resistance to sunlight, i.e. UV-light,    -   increased bulk density,    -   improved solubility,    -   bioavailability characteristics which are constant from one        batch to the other,    -   better flow and handling properties in the tableting process,    -   improved color stability, and    -   better filtration properties in the production process.

Therefore, by use of the crystalline forms of the present invention, itis possible to obtain galenic formulations having improved homogenicity,stability, purity and uniformity from one batch to the other.

Form I according to the invention has the characteristic IR absorptionspectra as shown in FIG. 1 and the characteristic X-ray diffractionpattern as shown in FIG. 12. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. Sample preparationwas performed generally as KBr disk. The spectra contains additionally aspecific acetone absorption band at 1709 cm⁻¹.

Form I can be further characterized with the aid of thermal analysismeasured in the range of 30° to 350° C. FIG. 28 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.Form I shows a desolvation process between 50° C. and 180° C. Analysisby thermogravimetry showed the presence of 10 weight-% to 11 weight-% ofacetone (theory of 1:1 solvate 10.82 weight-%). The DSC measurementgives a phase transition to form VII between 200° C. and 260° C. Thethermoanalytically resulting form VII melts between 280° C. and 290° C.

The molar ratio of acetone to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in said crystal modification is 1:1, that means thecompound of the invention in crystal modification of Form I is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride monoacetonate.

The invention also provides a process for preparing the above Form Iaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in acetone,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of 1N hydrochloric acid into the hydrochloride        salt at temperatures between 30° C. and the boiling point of        acetone, preferably between 40° C. and 50° C.,    -   (3) precipitation of Form I at room temperature, and    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride acetonate by filtration, and drying in vacuo at        room temperature.

Alternatively, Form I can be prepared according to a process whichcomprises:

-   -   (1) suspending Form III of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, which will be described later in detail, in        acetone,    -   (2) stirring at room temperature between a few hours or days,        preferably 10 to 20 days, and    -   (3) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran by filtration, and        drying in vacuo at room temperature.

Form II according to the invention has the characteristic IR absorptionspectra as shown in FIG. 2 and the characteristic X-ray diffractionpattern as shown in FIG. 13. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. The spectra as shownin the figures were converted to transmission.

Form II can be further characterized with the aid of thermal analysismeasured in the range of 30° to 350° C. FIG. 29 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.Form II shows a desolvation process between 120° C. and 180° C. Analysisby thermogravimetry showed the presence of 13 weight-% to 14 weight-% ofTHF (theory of 1:1 solvate 13.11 weight-%). The DSC measurement gives aphase transition to form VII between 200° C. and 260° C. Thethermoanalytically resulting form VII melts between 280° C. and 290° C.

The molar ratio of tetrahydrofuran to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in said crystal modification is 1:1, that means thecompound of the invention in crystal modification of Form II is amonosolvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with tetrahydrofuran.

The invention also provides a process for preparing the above Form IIaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in tetrahydrofuran,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of 1N hydrochloric acid into the hydrochloride        salt at temperatures between 10° C. and 60° C., preferably        between 20° C. and 30° C.,    -   (3) precipitation of Form II between −10° C. and 10° C., and    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran by filtration, and        drying in vacuo at room temperature.

Alternatively, Form II can be prepared according to a process whichcomprises:

-   -   (1) suspending Form III of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, which will be described later in detail, in        tetrahydrofuran,    -   (2) stirring at room temperature between a few hours or days,        preferably 15 to 30 days, and    -   (3) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride acetonate by filtration, and drying in vacuo at        room temperature.

Form XV according to the invention has the characteristic IR absorptionspectra as shown in FIG. 3 and the characteristic X-ray diffractionpattern as shown in FIG. 14. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. The spectra as shownin the figures were converted to transmission.

Form XV can be further characterized with the aid of thermal analysismeasured in the range of 30° to 350° C. FIG. 39 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.Form XV shows a desolvation process between 75° C. and 180° C. Analysisby thermogravimetry showed the presence of 13 weight-% to 14 weight-% ofTHF (theory of 1:1 solvate 13.11 weight-%). The DSC measurement gives aphase transition to form VII between 200° C. and 260° C. Thethermoanalytically resulting form VII melts between 280° C. and 290° C.The molar ratio of tetrahydrofuran to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in said crystal modification is 1:1, that means thecompound of the invention in crystal modification of Form XV is amonosolvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with tetrahydrofuran.

The invention also provides a process for preparing the above Form XVaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in tetrahydrofuran,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of 1N hydrochloric acid into the hydrochloride        salt at temperatures between −10° C. and 10° C., preferably        between −5° C. and +5° C.,    -   (3) precipitation of Form XV at room temperature, and    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran by filtration, and        drying in vacuo at room temperature.

Form X according to the invention has the characteristic X-raydiffraction pattern as shown in FIG. 15. XRD pattern were recorded usinga x-ray powder diffractometer (Bruker AXS D5000) in transmission mode(Cu K alpha 1, PSD).

The molar ratio of tetrahydrofuran to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in said crystal modification is 0, 5:1, that means thecompound of the invention in crystal modification of Form X is ahemisolvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with tetrahydrofuran.

The invention also provides a process for preparing the above Form Xaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in tetrahydrofuran,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of 1N hydrochloric acid into the hydrochloride        salt at temperatures between 10° C. and 40° C., preferably        between 20° C. and 30° C.,    -   (3) precipitation of Form X at room temperature, and    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran by filtration, and        drying at temperatures up to 80° C. maximum.

Form XI according to the invention has the characteristic IR absorptionspectra as shown in FIG. 4 and the characteristic X-ray diffractionpattern as shown in FIG. 16. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. The spectra as shownin the figures were converted to transmission.

Form XI can be further characterized with the aid of a thermal analysismeasured in the range of 30° to 350° C. FIG. 37 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.Form XI shows a desolvation process between 75° C. and 150° C. Analysisby thermogravimetry showed the presence of 6 weight-weight-% to 7weight-weight-% of methanol (theory of 1:1 solvate 6.28 weight-%). TheDSC measurement gives a phase transition to form VII between 200° C. and260° C. The thermoanalytically resulting form VII melts between 280° C.and 290° C.

The molar ratio of methanol to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in said crystal modification is 1:1, that means thecompound of the invention in the crystalline modification of Form XI isa monosolvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with methanol.

The invention also provides a process for preparing the above Form XIaccording to the invention, which comprises:

-   -   (1) suspending Form VI of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, which will be described later in detail, in        methanol at temperatures between 55° C. and the boiling point of        methanol,    -   (2) cooling down the reaction mixture to temperatures between        −40° and −10° C., preferably to −30° C., and    -   (3) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride methanolate by filtration at room temperature, and        drying in vacuo at room temperature.

Form XIV according to the invention has the characteristic IR absorptionspectra as shown in FIG. 5 and the characteristic X-ray diffractionpattern as shown in FIG. 17. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. The spectra as shownin the figures were converted to transmission.

Form XIV can be further characterized with the aid of a thermal analysismeasured in the range of 30° C. and 350° C. FIG. 38 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.Analysis by thermogravimetry showed the presence of 1 weight-% to 3weight-% of n-heptane (theory of 15:1 solvate 1.37 weight-%, theory of10:1 solvate 2.05 weight-%).

The molar ratio of n-heptane to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in said crystal modification is between 1:10 and 1:15,that means the compound of the invention in crystal modification of FormXIV is a solvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with n-heptane. The DSC measurement gives phasetransitions between 80° C. and 120° C. and between 200° C. and 260° C.The thermoanalytically resulting form VII melts between 280° C. and 290°C.

The invention also provides a process for preparing the above Form XIVaccording to the invention, which comprises:

-   -   (1) suspending Form III of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, which will be described later in detail, in        n-heptane,    -   (2) stirring at room temperature between a few hours or days,        preferably 15 to 30 days, and    -   (3) recovering the precipitated solvate of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride with n-heptane by filtration, and drying in vacuo        at room temperature.

Additionally, it has been found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is able to form hydrates in crystalline modifications.Preferably, the molar ratio of water to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is between 0, 25:1 to 2, 5:1, more preferably between 0,5:1 to 1:1, most preferably 1:1.

It should be understood that the present hydrates of the invention maycontain unbound water that is to say water which is other than water ofcrystallization.

Preferred forms of hydrates of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride include:

-   -   a)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride monohydrate in Form V; (as hereinafter defined),    -   b)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride in Form VI; (as hereinafter defined), and    -   c)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride hemihydrate in Form VIII; (as hereinafter        defined).

Form V according to the invention has the characteristic IR absorptionspectra as shown in FIG. 6 and the characteristic X-ray diffractionpattern as shown in FIG. 18. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. Sample preparationwas performed generally as KBr disk.

Form V can be further characterized with the aid of a thermal analysismeasured in the range of 30° to 350° C. FIG. 32 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.Form V shows a dehydration process between 25° C. and 100° C. Analysisby thermogravimetry showed the presence of 3 weight-% to 4 weight-% ofwater (theory of 1:1 solvate 3.63 weight-%). The DSC measurement gives aphase transition to form VII between 200° C. and 260° C. Thethermoanalytically resulting form VII melts between 280° C. and 290° C.

Form V of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride monohydrate according to the invention has surprisingadvantages with regard to its stability under conditions of highhumidity. Form V according to the invention is obtained as colorlesssolid substance in form of well defined crystals.

The invention also provides a process for preparing the above Form Vaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in tetrahydrofuran,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of aqueous hydrochloric acid into the        hydrochloride salt,    -   (3) precipitation of Form V at room temperature, and    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride monohydrate by filtration, and drying in vacuo at        room temperature.

Alternatively, Form V can be prepared according to a process whichcomprises:

-   -   (1) stirring of Form IV of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, which will be described later in detail, in water        with an amount of 5 to 10 times more relating to Form IV, and    -   (2) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride monohydrate by filtration, and drying in vacuo at        room temperature until the forming of the monohydrate of Form V        without excess of water.

Alternatively, Form V can be prepared according to a process whichcomprises:

-   -   (1) stirring of Form XIII of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        dihydrochloride, which will be described later in detail, in        water, and    -   (2) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride monohydrate by filtration, and drying in vacuo at        room temperature.

Form VI according to the invention has the characteristic IR absorptionspectra as shown in FIG. 7 and the characteristic X-ray diffractionpattern as shown in FIG. 19. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. Sample preparationwas performed generally as KBr disk.

Form VI can be further characterized with the aid of a thermal analysismeasured in the range of 30° to 350° C. FIG. 33 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.Form VI shows a dehydration process between 25° C. and 100° C. Analysisby thermogravimetry showed the presence of 6 weight-% to 7 weight-% ofwater (theory of 1:1.75 solvate 6.19 weight-%). The DSC measurementgives a phase transition to form VII between 200° C. and 260° C. Thethermoanalytically resulting form VII melts between 280° C. and 290° C.

The invention also provides a process for preparing the above Form VIaccording to the invention, which comprises:

-   -   (1) stirring of Form IV of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, which will be described later in detail, in water        in which the relative proportions of salt to water are between        1:5 and 1:10, and    -   (2) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride sesquihydrate by filtration, and drying in vacuo        at room temperature.

Alternatively, Form VI can be prepared according to a process whichcomprises:

-   -   (1) stirring of Form II of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, as described above, in water for one hour, and    -   (2) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride sesquihydrate by filtration, and drying in vacuo        at room temperature.

Form VIII according to the invention has the characteristic IRabsorption spectra as shown in FIG. 8 and the characteristic X-raydiffraction pattern as shown in FIG. 20. XRD pattern were recorded usinga x-ray powder diffractometer (Bruker AXS D5000) in transmission mode(Cu K alpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. Sample preparationwas performed generally as KBr disk.

Form VIII can be further characterized with the aid of a thermalanalysis measured in the range of 30° C. to 350° C. FIG. 35 shows theDSC (TA Instruments DSC 2920) and TGA (TA Instruments TGA 2950)measurements. Form VIII shows a dehydration process between 25° C. and125° C. Analysis by thermogravimetry showed the presence of 1 weight-%to 2 weight-% of water (theory of 1:0.5 solvate 1.85 weight-%). The DSCmeasurement gives a melting of resulted form IX around 268° C. Thethermoanalytically resulting form VII melts between 280° C. and 290° C.

The invention also provides a process for preparing the above Form VIIIaccording to the invention, which comprises:

-   -   (1) stirring of Form VI of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, as described above, in water for more than 12        hours, and    -   (2) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride hemihydrate by filtration, and drying in vacuo at        room temperature.

Alternatively, Form VIII can be prepared according to a process whichcomprises:

-   -   (1) stirring of Form II of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, as described above, in water for 12 hours, and    -   (2) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride hemihydrate by filtration, and drying in vacuo at        room temperature.

Additionally, it has been found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride form crystalline modifications as .anhydrates.

It should be understood that the present anhydrates of the invention maycontain unbound water that is to say water which is other than water ofcrystallization.

Preferred forms of anhydrates of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride include:

-   -   a)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride in Form IV (as hereinafter defined);    -   b)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride in Form III (as hereinafter defined);    -   c)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride in Form VII (as hereinafter defined); and    -   d)        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride in Form IX (as hereinafter defined).

Form IV according to the invention has the characteristic IR absorptionspectra as shown in FIG. 9 and the characteristic X-ray diffractionpattern as shown in FIG. 21. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. Sample preparationwas performed generally as KBr disk.

Form IV can be further characterized with the aid of a thermal analysismeasured in the range of 30° to 350° C. FIG. 31 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.The DSC measurement gives a phase transition to form VII between 200° C.and 260° C. The thermoanalytically resulting form VII melts between 280°C. and 290° C.

Owing to its crystalline properties, Form IV of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride according to the invention has surprising advantages withregard to its solubility and for its pharmaceutical processing intosolid dosage forms. The solubility of Form IV in water is 0.328 μg/ml.Form IV according to the invention is obtained as colorless solidsubstance in form of well defined crystals.

As shown in FIG. 27, Form IV is the most stable form at highertemperatures, e.g. >100° C.

The invention also provides a process for preparing the above Form IVaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in tetrahydrofuran,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of aqueous hydrochloric acid into the        hydrochloride salt at temperatures between 20° and 30° C.,    -   (3) precipitation of Form V at room temperature,    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride monohydrate Form V by filtration, and    -   (5) drying of Form V in vacuo at temperatures of 85° to 90° C.        to give Form IV.

Alternatively, Form IV can be prepared according to a process whichcomprises:

-   -   (1) drying of Form XI of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride monomethanolate, as described above, at        temperatures between 55° and 65° C. to give Form IV.

This particular polymorphic form (herein designated “Form IV”) hassuperior properties over other crystalline forms and is more suitablefor inclusion in pharmaceutical formulations.

Form III according to the invention has the characteristic IR absorptionspectra as shown in FIG. 10 and the characteristic X-ray diffractionpattern as shown in FIG. 22. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. Sample preparationwas performed generally as KBr disk.

Form III can be further characterized with the aid of a thermal analysismeasured in the range of 30° to 350° C. FIG. 30 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.The DSC measurement gives a phase transition to form VII between 200° C.and 260° C. The thermoanalytically resulting form VII melts between 280°C. and 290°.

Owing to its crystalline properties, Form III of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride according to the invention is the most stable form at roomtemperature, that means the thermodynamically stable form at roomtemperature (FIG. 27). Form III according to the invention is obtainedas colorless solid substance in form of well defined crystals.

The invention also provides a process for preparing the above Form IIIaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in tetrahydrofuran,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of 1N hydrochloric acid into the hydrochloride        salt at temperatures between 10° C. and 40° C., preferably        between 20° C. and 30° C.,    -   (3) precipitation of Form II at room temperature,    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride solvate with tetrahydrofuran by filtration, and    -   (5) drying of Form II in vacuo at temperatures of at least        100° C. to give Form III.

Form VII according to the invention has the characteristic IR absorptionspectra as shown in FIG. 11 and the characteristic X-ray diffractionpattern as shown in FIG. 23. XRD pattern were recorded using a x-raypowder diffractometer (Bruker AXS D5000) in transmission mode (Cu Kalpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm⁻¹on a Bruker IFS48. Spectral resolution was 2 cm⁻¹. Sample preparationwas performed generally as KBr disk.

Form VII can be further characterized with the aid of a thermal analysismeasured in the range of 30° to 350° C. FIG. 34 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.The DSC measurement indicates the melting point of the pure Form VII at288° C.

Form VII is the high temperature form of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride according to the invention. Form VII according to theinvention is obtained as colorless solid substance in form of welldefined crystals.

The invention also provides a process for preparing the above Form VIIaccording to the invention, which comprises:

-   -   (1) tempering Form IV of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, as described above, at temperatures of at least        200° C., preferably at 250° C., for 30 minutes.

Form IX according to the invention has the characteristic X-raydiffraction pattern as shown in FIG. 24. XRD pattern were recorded usinga x-ray powder diffractometer (Bruker AXS D5000) in transmission mode(Cu K alpha 1, PSD).

Form IX can be further characterized with the aid of a thermal analysismeasured in the range of 30° to 350° C. FIG. 36 shows the DSC (TAInstruments DSC 2920) and TGA (TA Instruments TGA 2950) measurements.The DSC measurement gives of the melting of form IX at 267° C. followedby a recrystallization to form VII. The thermoanalytically resultingform VII melts between 280° C. and 290° C.

Form IX according to the invention is obtained as colorless solidsubstance in form of well defined crystals.

The invention also provides a process for preparing the above Form IXaccording to the invention, which comprises:

-   -   (1) drying of Form VIII of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride, as described above, at temperatures between        90° C. and 110° C. to give Form IX.

Additionally, it has been found that1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinedihydrochloride form crystalline modifications.

It should be understood that the present dihydrochlorides of theinvention may contain unbound water that is to say water which is otherthan water of crystallization.

A preferred form of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinedihydrochloride is1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinedihydrochloride in Form XIII; (as hereinafter defined).

Form XIII (dihydrochloride) according to the invention has thecharacteristic X-ray diffraction pattern as shown in FIG. 25. XRDpattern were recorded using a x-ray powder diffractometer (Bruker AXSD5000) in transmission mode (Cu K alpha 1, PSD).

Form XIII according to the invention is obtained as colorless solidsubstance in form of well defined crystals.

The invention also provides a process for preparing the above Form XIIIaccording to the invention, which comprises:

-   -   (1) dispersing        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        in an organic solvent chosen from the group consisting of        tetrahydrofuran, ethanol, isopropanol or mixtures thereof with        water,    -   (2) converting the        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        base, by addition of 2N or concentrated hydrochloric acid into        the hydrochloride salt at temperatures between 20° and 30° C.,    -   (3) precipitation of Form XIII at room temperature,    -   (4) recovering the precipitated        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        dihydrochloride Form XIII by filtration, and    -   (5) drying of Form XIII in vacuo at room temperature.

Preferably, the solvates of the present invention are in a form having adense crystalline structure which enables the raw active ingredient tobe easily formulated into final dosage form.

Additionally, Form XVI of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride has been found.

Form XVI according to the invention has the characteristic X-raydiffraction pattern as shown in FIG. 26. XRD pattern were recorded usinga x-ray powder diffractometer (Bruker AXS D5000) in transmission mode(Cu K alpha 1, PSD).

The invention also provides a process for preparing the above Form XVIaccording to the invention, which comprises:

-   -   (1) dissolving        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride in acetonitrile and water in the molar ratio 1:1,        and    -   (2) freeze-drying or spray-drying overnight to give Form XVI of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride.

Similarly, the freeze-dry process can be performed in other mixtures ofwater miscible organic solvent (tetrahydrofuran, alcohols,N-methylpyrrolidon) with water.

Additionally, a pure amorphous Form of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride has been found.

It has been found that due to the solubility and bioavailabilityproperties, Form II and Form VIII are useful as an ingredient ofextended release formulations. Form II is especially useful as aningredient of extended release formulations.

These Forms of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride or dihydrochloride, as referred to as Forms I, II, III,IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV and XVI respectively andall of which are hereinafter referred to as the “products of theinvention” can be used to treat and prevent the disorders:

depressive disorders, including the sub-type disorders major depressivedisorder and dysthymic disorder, adolescent depression, anxietydisorders, including the sub-type anxiety disorders chosen from thesub-types panic disorder with and/or without agoraphobia, agoraphobia,obsessive-compulsive spectrum disorders, social phobia, specific phobiaincluding neophobia, posttraumatic stress disorder, acute stressindication or generalized-anxiety disorder, bipolar disorders, mania,dementia, including Alzheimer's disease and multi-infarct,substance-related disorders, sexual dysfunctions including prematureejaculation, eating disorders including anorexia nervosa and bulimianervosa and/or obesity, fibromyalgia, chronic pain, sleeping disordersincluding dyssomnias and narcolepsy, psychiatric disorders likepsychoses, schizophrenia or schizoaffective disorder, cerebral infarctlike stroke and cerebral ischemia, CNS disorders such as tension. Theyare also useful for the therapy of side-effects in the treatment ofhypertension (e.g. with α-methyldopa) and for the prophylaxis andtherapy of cerebral disorders, in endocrinology and gynecology, e.g. forthe treatment of acromegaly, hypogonadism, secondary amenorrhea,premenstrual syndrome or undesired puerperal lactation.

These disorders are herein after referred to as “the Disorders.”

The present invention further provides pharmaceutical compositions ormedicaments comprising a Product of the Invention. The pharmaceuticalcomposition may comprise additionally one or more conventional auxiliarysubstances and/or carriers.

Thus, the Products of the Invention can be formulated into theconventional forms of administration, including peroral and parenteralforms of administration. Tablets or capsules are preferred formulations.They can be produced by conventional mixing processes and with the useof conventional auxiliary substances and carriers, as well as binders,disintegrants, flavorings and the like. The dose corresponds to thatmentioned in U.S. Pat. No. 5,532,241.

Additionally, the invention relates to the use of a pharmaceuticalcomposition containing at least one product of the invention for thetreatment of the Disorders.

The following compositions are preferred:

-   -   A Composition comprising Form IV and Form V,    -   A Composition comprising Form IV and Form V in a molar ratio of        about 100 to 1 to 10 to 1,    -   A Pharmaceutical preparation comprising an active ingredient        consisting essentially of a mixture of Form IV and Form V, and    -   A Pharmaceutical preparation comprising an active ingredient        consisting essentially of a mixture of Form IV and Form V in a        molar ratio of about 100 to 1 to 10 to 1.

An extended release formulation comprising Form I and/or Form III and/orform VIII is also preferred.

Furthermore, the present invention relates to the use of Products of theInvention for the manufacture of a medicament for the treatment of andprevention of the Disorders, such as depressive disorders, adolescentdepression, anxiety disorders, bipolar disorders, mania, dementia,substance-related disorders, sexual dysfunctions, eating disorders,obesity, fibromyalgia, chronic pain, sleeping disorders, psychiatricdisorders, cerebral infarct, tension, for the therapy of side-effects inthe treatment of hypertension, cerebral disorders, chronic pain,acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndromeand undesired puerperal lactation.

The present invention further provides a method for treating and/orpreventing any one or more of the Disorders by administering aneffective and/or prophylactic amount of the Products of the Invention toa patient in need thereof.

Preferably, the Disorders which are treated are depression, anxietydisorders, more preferably social anxiety disorder, panic disordergeneralized anxiety disorder, posttraumatic stress disorder and/orobsessive compulsive disorder.

Accordingly, the present invention is further concerned withpharmaceutical formulations comprising this polymorphic form as anactive ingredient, and the use of this polymorphic form and itsformulations in the treatment of certain disorders.

For the treatment of certain conditions it may be desirable to employthe specific crystalline forms of the present invention in conjunctionwith another pharmacologically active agent. It will be appreciated thatthe compound of the present invention may be presented together withanother therapeutic agent as a combined preparation for simultaneous,separate or sequential use for the relief of emesis. Such combinedpreparations may be, for example, in the form of a twin pack.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preferred specific embodiments and examples are,therefore, to be construed as merely illustrative, and not limitative tothe remainder of the disclosure in any way whatsoever.

The entire disclosures of all applications, patents, and publicationscited above and below, are hereby incorporated by reference.

EXAMPLES Example 1

Production of Form I of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride:

Method 1:

1 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineis dissolved in 80 ml of acetone. The temperature of the solution isallowed to come to 50° C. and 0.5 ml of 1N hydrochloric acid is added tothe reaction mixture. After stirring for 2 to 3 minutes the reactionmixture is cooled to room temperature and precipitation occurs. Suctionfiltration of the precipitated crystals is effected. Drying in vacuo atroom temperature to constant weight leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride acetonate Form I.

Method 2:

2.25 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Form III are dispersed in 200 ml of acetone. Afterstirring for 14 days the precipitated crystals are recovered byfiltration, and drying in vacuo at room temperature to constant weightleads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride acetonate Form I which present the IR absorption spectraof FIG. 1 and the x-ray diffraction spectrum of FIG. 12.

Example 2 Production of Form II of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Method 1:

1 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazineis dissolved in 46.6 g tetrahydrofuran and 2.2 g 1N hydrochloric acid isadded to the reaction mixture. After precipitation and stirring for 30minutes suction filtration of the precipitated crystals is effected.Drying in vacuo at room temperature to constant weight leads to themonosolvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with tetrahydrofuran of Form II which present the IRabsorption spectra of FIG. 2 and the x-ray diffraction spectrum of FIG.13.

Method 2:

3 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Form III are dispersed in 400 ml of tetrahydrofuran. Afterstirring for 20 days the precipitated crystals are recovered byfiltration. Drying in vacuo at room temperature to constant weight leadsto the solvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with tetrahydrofuran of Form II.

Example 3 Production of Form XV of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride

10 ml of 1N hydrochlorid acid are added to a solution of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride in tetrahydrofuran [200 ml] (molar ratio base totetrahydrofuran=1:48) at 0° C. After stirring for 30 min theprecipitated crystals are recovered by filtration. Drying in vacuo atroom temperature to constant weight leads to the solvate of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride with tetrahydrofuran of Form XV which present the IRabsorption spectra of FIG. 3 and the x-ray diffraction spectrum of FIG.14.

Example 4 Production of Form X of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride

-   -   8.6 g of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        is dissolved in tetrahydrofuran and 19.4 ml 1N hydrochloric acid        and 7.4 ml water are added within 30 minutes to this solution at        35-37° C. After stirring of five hours, precipitation occurs and        suction filtration is effected. Drying in vacuo at room        temperature to constant weight leads to the solvate of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride with tetrahydrofuran of Form X which present the        x-ray diffraction spectrum of FIG. 15.

Example 5 Production of Form XI of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride

-   -   3 g of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride Form IV are dispersed in 500 ml of methanol at        60° C. The reaction mixture is cooled to −30° C. and        precipitation occurs. Suction filtration of the precipitated        crystals is effected at room temperature. Drying in vacuo to        constant weight leads to        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride methanolate of Form XI which present the IR        absorption spectra of FIG. 4 and the x-ray diffraction spectrum        of FIG. 16.

Example 6 Production of Form XIV of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride

-   -   3.6 g of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride Form III are dispersed in 75 ml of n-heptane.        After stirring for three weeks suction filtration of the        precipitated crystals is effected at room temperature. Drying in        vacuo to constant weight at room temperature leads to the        solvate of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        hydrochloride with n-heptane of Form XIV which present the IR        absorption spectra of FIG. 5 and the x-ray diffraction spectrum        of FIG. 17.

Example 7 Production of Form V of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Method 1:

To a solution of 1 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinein 32.6 g tetrahydrofuran 2.1 g hydrochloric acid (37 weight-%) areadded. After stirring suction filtration of the precipitated crystals iseffected. Drying in vacuo to constant weight at room temperature leadsto1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrate of Form V which present the IR absorption spectraof FIG. 6 and the x-ray diffraction spectrum of FIG. 18.

Method 2:

2.25 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Form IV are dispersed in 10 bis 20 g water. After stirringfor 24 to 48 hours the crystals are recovered by filtration, and dryingin vacuo to constant weight at room temperature leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrate of Form V.

Method 3:

10 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinedihydrochloride Form XIII are dispersed in 11 water. After stirring for48 hours the crystals are recovered by filtration, and drying in vacuoto constant weight at room temperature leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrate of Form V.

Example 8 Production of Form VI of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Method 2:

10 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Form II are dispersed in 100 ml water. After stirring for1 hour the crystals are recovered by filtration, and drying in vacuo toconstant weight at room temperature leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrate of Form VI.

Example 9 Production of Form VIII of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Method 1:

1 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Form VI are dispersed in 10 ml water. After stirring for12 hours the crystals are recovered by filtration, and drying in vacuoto constant weight at room temperature leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrate of Form VIII which present the IR absorptionspectra of FIG. 8 and the x-ray diffraction spectrum of FIG. 20.

Method 2:

10 g of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Form II are dispersed in 10 to 20 g water. After stirringfor more than 1 hour the crystals are recovered by filtration, anddrying in vacuo to constant weight at room temperature leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hydrate of Form VIII. (After stirring for about 1 hourForm VI occurs as an intermediate which is subsequently converted intoForm VIII)

Example 10 Production of Form IV of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride Method 1:

Drying of Form V prepared according to example 7 in vacuo to constantweight at 85° to 90° C. leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride of Form IV which present the IR absorption spectra of FIG.9 and the x-ray diffraction spectrum of FIG. 21.

Method 2:

Drying of Form XI prepared according to example 5 in vacuo to constantweight at 60° C. leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride of Form IV.

Example 11 Production of Form III of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride

Drying of Form II prepared according to example 2 in vacuo to constantweight at 100° to 110° C. leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride of Form III which present the IR absorption spectra ofFIG. 10 and the x-ray diffraction spectrum of FIG. 22.

Example 12 Production of Form VII of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride

Tempering of Form IV prepared according to example 10 for 10 minutes at250° C. leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride of Form VII which present the IR absorption spectra ofFIG. 11 and the x-ray diffraction spectrum of FIG. 23.

Example 13 Production of Form IX of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride

Drying of Form VIII prepared according to example 9 in vacuo to constantweight at 100° to 110° C. leads to1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride of Form IX which present the x-ray diffraction spectrum ofFIG. 24.

Example 14 Production of Form XIII of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinedihydrochloride

-   -   3 g of        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        is dissolved in 100 ml of tetrahydrofuran and 10 ml of 2N or        concentrated hydrochloric acid. After stirring for 2 to 3        minutes suction filtration of the precipitated crystals is        effected. Drying in vacuo at room temperature to constant weight        leads to        1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine        dihydrochloride of Form XIII which present the characteristic        x-ray diffraction spectrum of FIG. 25.

Example 15

Production of Form XVI of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride:

Method 1: Freeze-Dry

500 mg of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride of Form IV, III, VII or IX are dissolved in a mixture of100 ml acetonitril and 100 ml water. The solution is freeze-dried overnight to yield 500 mg of a white powder which present the characteristicx-ray diffraction spectrum of FIG. 26.

Advantage:1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride is better soluble in the solvent mixture than in eachsolvent alone. Similarly the freeze-dry process can be performed inother mixtures of water miscible organic solvent (tetrahydrofuran,alcohols, N-methylpyrrolidon) with water.

Method 2: b) Spray-Dry

500 mg1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride of Form IV, III, VII or IX are dissolved in a mixture of100 ml acetonitril and 100 ml water. The solution is spray-dried toyield Form XVI.

Example 16

Solubility data of Forms II, III, IV, V, VI and VIII are measuredaccording to Alex Avdeef et al., Pharm. Pharmacol. Commun., 1998,4:165-178 and Alex Avdeef et al., Pharmaceutical Research, 2000,17:85-89 via potentiometric titration.

The pSOLTM solubility profiler, automatically collects potentiometricdata, calculates the pH-solubility profiles, and prints the values at0.1 pH unit intervals. Intrinsic solubilities in the milli-, micro- andnanogram levels can be determined. Also presented are two new concepts,the Flux Factor Profile and Dose Limit Profile. Both concepts follow theguidelines consistent with the BioPharmaceutics Classification Scheme.

TABLE II Solubility data in μg/ml Form Form I Form II Form III Form IVForm V Form VI VIII 0.08 0.03 0.12 0.33 0.18 0.23 0.10

Below are given the most relevant peaks of the IR-spectra of theindividual Forms:

Form I

3459 (m), 3335 (w), 3271 (m), 3252 (w), 3202 (m), 3180 (m), 3148 (m),3039 (w), 3009 (w), 2941 (m), 2868 (m), 2847 (m), 2660 (m), 2579 (m),2487 (w), 2451 (m), 2212 (m), 1761 (w), 1711 (s), 1673 (s), 1617 (m),1597 (s), 1577 (m), 1473 (m), 1468 (m), 1444 (m), 1423 (w), 1400 (m),1364 (s), 1319 (w), 1302 (w), 1279 (w), 1265 (m), 1244 (w), 1225 (s),1197 (w), 1184 (m), 1171 (m), 1136 (w), 1115 (m), 1100 (m), 1093 (sh),1034 (w), 1013 (w), 973 (w), 956 (m), 939 (m), 925 (w), 881 (m), 864(m), 841 (w), 832 (w), 821 (m), 801 (m), 762 (m), 738 (m), 730 (w), 689(sh), 673 (m), 644 (m), 622 (w), 607 (w), 580 (w), 543 (w), 534 (w), 508(m), 500 (m), 491 (m), 471 (w), 454 (w).

Form II

3458 (m), 3424 (sh), 3348 (w), 3277 (w), 3204 (m), 3184 (m), 3036 (w),3008 (w), 2972 (sh), 2938 (m), 2863 (m), 2659 (m), 2597 (m), 2579 (m),2556 (m), 2459 (m), 2210 (m), 1736 (w), 1677 (s), 1618 (m), 1601 (s),1578 (m), 1552 (sh), 1474 (m), 1446 (m), 1402 (m), 1376 (m), 1368 (m),1320 (m), 1302 (w), 1275 (w), 1262 (m), 1250 (m), 1221 (m), 1198 (w),1186 (m), 1169 (m), 1156 (w), 1131 (w), 1116 (w), 1101 (w), 1065 (m),1034 (w), 1011 (w), 974 (w), 955 (m), 941 (m), 925 (w), 913 (w), 881(m), 859 (w), 833 (w), 817 (w), 809 (w), 800 (m), 762 (w), 739 (w), 694(w), 676 (w), 640 (m), 607 (w), 583 (w), 542 (w), 506 (w), 495 (w), 455(w).

Form III

3460 (m), 3337 (w), 3269 (m), 3257 (m), 3177 (m), 3145 (m), 3061 (m),3033 (m), 3001 (w), 2936 (m), 2922 (sh), 2865 (m), 2837 (w), 2787 (w),2655 (m), 2591 (m), 2457 (m), 2218 (m), 1674 (s), 1618 (m), 1598 (s),1577 (m), 1473 (m), 1463 (m), 1453 (sh), 1445 (m), 1402 (m), 1380 (m),1368 (m), 1356 (m), 1329 (m), 1320 (m), 1304 (w), 1284 (w), 1265 (m),1256 (m), 1240 (m), 1226 (m), 1215 (m), 1186 (m), 1172 (m), 1124 (m),1097 (m), 1088 (sh), 1059 (w), 1035 (w), 987 (w), 955 (m), 941 (m), 924(w), 918 (sh), 879 (m), 853 (w), 835 (w), 809 (m), 800 (m), 784 (w), 762(m), 736 (w), 677 (w), 659 (w), 629 (m), 608 (w), 581 (w), 544 (w), 495(w), 478 (m), 454 (w).

Form IV

3437 (m), 3328 (w), 3273 (w), 3030 (m), 3006 (m), 2987 (m), 2938 (m),2915 (m), 2875 (m), 2845 (m), 2660 (m), 2459 (m), 2222 (s), 1899 (w),1670 (s), 1602 (s), 1577 (s), 1475 (m), 1444 (s), 1370 (s), 1320 (m),1304 (m), 1281 (m), 1275 (m), 1249 (m), 1227 (s), 1186 (m), 1162 (m),1141 (w), 1131 (w), 1112 (m), 1099 (w), 1082 (w), 1032 (w), 971 (w), 951(m), 942 (m), 909 (w), 881 (m), 854 (w), 822 (m), 768 (w), 733 (w), 691(w), 660 (w), 642 (w), 628 (w), 607 (w), 581 (w), 526 (m), 502 (w), 493(w), 471 (w), 461 (w).

Form V

3483 (s), 3460 (s), 3222 (s), 3192 (m), 3007 (w), 2947 (m), 2864 (w),2838 (w), 2784 (w), 2682 (m), 2606 (m), 2478 (w), 2461 (w), 2219 (m),1669 (s), 1604 (s), 1575 (m), 1474 (m), 1461 (m), 1444 (m), 1402 (m),1382 (m), 1371 (sh), 1362 (m), 1321 (w), 1304 (w), 1271 (m), 1263 (sh),1247 (m), 1226 (m), 1185 (m), 1160 (m), 1137 (w), 1113 (m), 1101 (w),1091 (w), 1082 (w), 1058 (w), 1048 (w), 1030 (w), 1008 (w), 972 (w), 954(m), 942 (m), 917 (w), 883 (w), 857 (w), 822 (m), 815 (m), 767 (w), 739(w), 682 (w), 661 (w), 641 (w), 624 (w), 591 (w), 583 (w), 529 (m), 499(w).

Form VI

3410 (s), 3334 (sh), 3271 (s), 3217 (s), 3188 (s), 3172 (s), 3032 (sh),2938 (m), 2915 (m), 2846 (m), 2675 (m), 2581 (m), 2539 (sh), 2449 (m),2216 (s), 1670 (s), 1603 (s), 1593 (s), 1577 (s), 1470 (m), 1444 (s),1397 (m), 1381 (s), 1369 (sh), 1350 (m), 1323 (m), 1304 (m), 1272 (m),1247 (m), 1219 (s), 1187 (m), 1164 (m), 1132 (m), 1120 (m), 1099 (m),1030 (w), 1008 (w), 983 (w), 960 (m), 942 (m), 920 (w), 887 (m), 854(w), 838 (w), 815 (m), 776 (sh), 767 (w), 739 (w), 727 (sh), 677 (w),655 (w), 635 (m), 607 (w), 542 (w), 530 (w), 499 (w), 472 (w), 426 (w).

Form VII

3480 (sh), 3459 (s), 3166 (m), 3146 (m), 3031 (m), 3007 (m), 2926 (m),2870 (sh), 2853 (m), 2664 (m), 2570 (m), 2540 (sh), 2460 (m), 2221 (m),1673 (s), 1613 (sh), 1592 (s), 1578 (sh), 1552 (m), 1475 (m), 1445 (m),1398 (m), 1366 (m), 1319 (m), 1303 (m), 1275 (m), 1248 (m), 1226 (m),1187 (m), 1177 (m), 1161 (m), 1133 (w), 1114 (w), 1101 (w), 1033 (w),1009 (w), 973 (w), 952 (m), 942 (m), 925 (w), 919 (w), 882 (m), 855 (w),823 (m), 815 (m), 769 (w), 735 (w), 690 (w), 642 (m), 627 (w), 608 (w),581 (w), 571 (w), 559 (w), 547 (w), 501 (w).

Form VIII

3379 (m), 3342 (m), 3298 (m), 3234 (m), 3188 (s), 3141 (s), 3027 (w),2938 (m), 2866 (w), 2844 (m), 2787 (w), 2729 (w), 2679 (m), 2598 (m),2210 (s), 1658 (s), 1611 (s), 1576 (w), 1556 (m), 1472 (m), 1464 (m),1443 (s), 1404 (s), 1385 (sh), 1369 (m), 1331 (sh), 1321 (m), 1302 (w),1286 (w), 1264 (w), 1249 (m), 1230 (s), 1177 (m), 1162 (m), 1128 (w),1117 (w), 1099 (w), 1084 (w), 1033 (w), 1008 (w), 971 (w), 958 (m), 941(m), 926 (w), 917 (w), 898 (w), 882 (w), 870 (w), 857 (w), 836 (w), 826(w), 803 (s), 767 (w), 733 (w), 687 (m), 655 (w), 641 (m), 618 (w), 599(w), 554 (w), 535 (w), 503 (w), 493 (w), 470 (w), 439 (w).

Form XI

3415 (s), 3290 (m), 3282 (m), 3234 (s), 3196 (s), 3176 (s), 3005 (m),2993 (m), 2938 (m), 2849 (m), 2678 (m), 2629 (m), 2592 (m), 2473 (m),2457 (m), 2217 (s), 1680 (s), 1673 (s), 1608 (s), 1594 (sh), 1576 (s),1474 (m), 1457 (sh), 1440 (s), 1427 (sh), 1401 (m), 1372 (m), 1365 (m),1354 (m), 1321 (m), 1304 (sh), 1281 (m), 1263 (w), 1247 (m), 1236 (m),1222 (s), 1185 (m), 1175 (m), 1169 (m), 1160 (sh), 1128 (m), 1121 (m),1100 (m), 1086 (m), 1032 (w), 1019 (w), 978 (w), 958 (m), 942 (m), 921(w), 893 (w), 884 (m), 856 (m), 813 (m), 775 (w), 764 (w), 739 (w), 731(w), 699 (w), 673 (m), 658 (w), 634 (m), 608 (m), 567 (m), 544 (m), 535(w), 502 (w), 492 (w), 476 (w), 466 (w), 455 (w).

Form XIV

3458 (s), 2923 (m), 2853 (m), 2696 (w), 2595 (w), 2456 (w), 2218 (m),1674 (s), 1617 (m), 1598 (s), 1580 (sh), 1559 (sh), 1472 (m), 1445 (m),1401 (m), 1383 (m), 1369 (m), 1321 (m), 1304 (w), 1263 (sh), 1240 (m),1226 (m), 1216 (m), 1186 (m), 1169 (m), 1159 (m), 1123 (m), 1096 (m),1057 (w), 1034 (w), 986 (w), 956 (m), 941 (m), 924 (w), 883 (w), 864(w), 853 (m), 810 (m), 801 (m), 762 (m), 735 (m), 641 (w), 629 (m), 501(m).

Form XV

3458 (s), 3281 (m), 3227 (m), 3187 (sh), 2935 (m), 2925 (sh), 2866 (w),2701 (w), 2594 (w), 2455 (w), 2217 (m), 1675 (s), 1617 (m), 1598 (m),1578 (m), 1472 (m), 1444 (m), 1401 (m), 1380 (m), 1369 (m), 1357 (sh),1320 (w), 1303 (w), 1265 (m), 1241 (m), 1227 (m), 1215 (m), 1203 (w),1186 (w), 1172 (m), 1123 (w), 1097 (w), 1087 (w), 1032 (w), 986 (w), 956(w), 941 (m), 924 (w), 882 (w), 853 (w), 835 (w), 812 (w), 802 (w), 762(w), 736 (w), 676 (w), 641 (w), 630 (w).

Below are given the most relevant peaks of the Raman-spectra of theindividual Forms with an estimated accuracy of +/−5 cm⁻¹:

Form I:

3128 (m), 3071 (m), 3044 (w), 3011 (w), 2993 (m), 2975 (m), 2956 (m),2912 (m), 2868 (m), 2849 (m), 2214 (s), 1674 (m), 1618 (m), 1594 (s),1578 (s), 1553 (m), 1475 (w), 1446 (m), 1400 (w), 1367 (m), 1347 (m),1337 (m), 1322 (m), 1303 (m), 1282 (m), 1267 (m), 1244 (s), 1229 (m),1184 (m), 1174 (m), 1138 (m), 1097 (m), 1052 (m), 1033 (m), 1014 (m),974 (w), 957 (w), 940 (m), 925 (w), 914 (w), 881 (m), 836 (w), 818 (m),794 (w), 783 (w), 767 (w), 753 (w), 729 (w), 693 (w), 674 (w), 658 (w),644 (w), 625 (w), 608 (w), 587 (w), 581 (w), 540 (w), 503 (w), 492 (w),477 (w), 443 (w), 438 (w), 407 (w), 380 (w), 328 (w), 298 (w), 268 (w),252 (w), 230 (w), 211 (w).

Form II:

3128 (w), 3113 (w), 3068 (m), 3040 (w), 3031 (w), 2992 (m), 2974 (m),2957 (m), 2905 (m), 2865 (m), 2850 (m), 2222 (m), 2210 (s), 1679 (m),1617 (m), 1603 (s), 1579 (s), 1552 (m), 1476 (w), 1447 (m), 1404 (w),1369 (m), 1358 (m), 1347 (m), 1323 (m), 1304 (m), 1277 (m), 1266 (m),1245 (m), 1233 (w), 1220 (w), 1186 (m), 1176 (m), 1134 (w), 1102 (w),1051 (m), 1033 (m), 1010 (w), 974 (w), 957 (w), 942 (m), 927 (w), 917(w), 882 (m), 862 (w), 846 (w), 830 (m), 819 (m), 786 (w), 767 (w), 755(w), 735 (w), 695 (w), 679 (w), 661 (w), 641 (w), 632 (w), 608 (w), 586(w), 541 (w), 506 (w), 495 (w), 477 (w), 447 (w), 438 (w), 405 (w), 379(w), 330 (w), 298 (w), 270 (w), 255 (w), 228 (w), 212 (m).

Form III:

3128 (w), 3087 (sh), 3061 (m), 2995 (m), 2984 (m), 2966 (m), 2957 (m),2939 (m), 2916 (m), 2867 (m), 2790 (w), 2220 (s), 1675 (m), 1619 (s),1595 (s), 1579 (s), 1554 (m), 1476 (w), 1446 (m), 1404 (w), 1376 (w),1352 (m), 1328 (m), 1303 (m), 1285 (m), 1272 (m), 1266 (m), 1247 (s),1228 (w), 1215 (w), 1170 (m), 1137 (w), 1098 (m), 1058 (w), 1034 (w),989 (w), 957 (m), 942 (m), 924 (m), 884 (m), 858 (w), 839 (m), 826 (m),783 (w), 752 (w), 731 (w), 702 (w), 678 (w), 659 (w), 628 (w), 609 (w),581 (w), 563 (w), 546 (w), 496 (w), 482 (w), 469 (w), 444 (w), 409 (m),367 (w), 352 (w), 328 (w), 285 (w), 264 (w), 249 (w), 212 (m).

Form IV:

3160 (w), 3145 (w), 3109 (m), 3073 (m), 3008 (w), 2987 (m), 2973 (m),2959 (w), 2936 (w), 2910 (m), 2870 (w), 2849 (m), 2797 (w), 2226 (s),1665 (w), 1622 (m), 1588 (s), 1549 (m), 1478 (m), 1445 (m), 1410 (w),1355 (m), 1346 (m), 1322 (m), 1277 (m), 1252 (m), 1189 (m), 1144 (w),1116 (m), 1049 (w), 1034 (w), 1005 (w), 973 (w), 943 (m), 927 (w), 916(w), 883 (m), 831 (m), 817 (w), 770 (w), 757 (w), 736 (w), 695 (w), 685(w), 661 (w), 642 (w), 628 (w), 610 (w), 587 (w), 536 (w), 504 (w), 493(w), 475 (w), 460 (w), 439 (w), 409 (w), 390 (w), 344 (w), 317 (w), 277(w), 248 (w), 223 (w).

Form V:

3112 (w), 3091 (m), 3074 (m), 3028 (w), 3004 (w), 2081 (m), 2933 (w),2919 (m), 2866 (w), 2841 (w), 2787 (w), 2222 (s), 1663 (w), 1618 (m),1607 (m), 1577 (s), 1552 (m), 1478 (m), 1440 (m), 1406 (w), 1381 (m),1358 (m), 1342 (m), 1321 (m), 1307 (m), 1276 (m), 1252 (m), 1235 (m),1189 (m), 1143 (w), 1105 (w), 1092 (w), 1052 (w), 1012 (w), 974 (w), 944(m), 927 (w), 918 (w), 885 (m), 860 (w), 847 (w), 830 (m), 771 (m), 757(w), 736 (w), 696 (w), 684 (w), 660 (w), 642 (w), 626 (w), 610 (w), 583(w), 541 (m), 501 (w), 478 (w), 441 (w), 410 (w), 381 (w), 323 (w), 302(w), 282 (w), 239 (w), 226 (w).

Form XI:

3133 (m), 3094 (w), 3078 (m), 3060 (m), 3004 (w), 2989 (m), 2968 (m),2943 (m), 2923 (w), 2897 (m), 2871 (w), 2852 (w), 2835 (w), 2221 (s),1676 (m), 1613 (s), 1578 (s), 1544 (m), 1473 (m), 1447 (m), 1424 (m),1401 (w), 1375 (m), 1353 (m), 1342 (m), 1325 (m), 1302 (m), 1279 (m),1264 (m), 1246 (m), 1233 (m), 1222 (w), 1197 (w), 1186 (w), 1171 (m),1130 (w), 1102 (w), 1078 (m), 1049 (w), 1018 (w), 983 (w), 959 (w), 942(m), 923 (m), 886 (m), 857 (w), 838 (m), 817 (m), 765 (w), 749 (w), 733(w), 698 (w), 673 (w), 658 (w), 634 (w), 627 (w), 609 (w), 566 (w), 546(w), 535 (w), 503 (w), 492 (w), 481 (w), 467 (w), 440 (w), 432 (w), 406(m), 366 (w), 354 (w), 327 (w), 285 (w), 241 (w).

Form XIV:

3128 (w), 3061 (m), 3002 (m), 2995 (m), 2983 (w), 2966 (m), 2957 (m),2938 (m), 2914 (m), 2867 (m), 2219 (s), 1675 (m), 1619 (s), 1596 (s),1579 (s), 1554 (m), 1475 (w), 1446 (m), 1404 (w), 1374 (w), 1352 (m),1329 (w), 1322 (w), 1303 (m), 1285 (m), 1273 (m), 1265 (m), 1247 (m),1228 (w), 1216 (w), 1204 (w), 1187 (w), 1170 (m), 1137 (w), 1098 (m),1058 (w), 1034 (w), 989 (w), 958 (w), 942 (m), 924 (m), 884 (m), 858(w), 840 (m), 825 (w), 782 (w), 752 (w), 732 (w), 701 (w), 678 (w), 657(w), 629 (w), 609 (w), 581 (w), 563 (w), 546 (w), 536 (w), 496 (w), 482(w), 469 (w), 443 (w), 409 (m), 397 (w), 367 (w), 328 (w), 319 (w), 286(w), 265 (w), 248 (w), 212 (w).

TABLE III Data of powder-XRD-pattern of polymorphic Forms. (10characteristic peaks of each polymorph have been taken for evaluation.The XRD instrument is controlled for 2Theta ± 0.1°). No. d (Å) 2θ I/I₀Form I: 1 8,501 10.40 21 2 7,898 11.19 17 3 6,606 13.39 31 4 6,532 13.5425 5 6,416 13.79 26 6 5,590 15.84 28 7 4,210 21.09 63 8 3,761 23.64 18 93,632 24.49 100 10 3,452 25.79 26 Form II: 1 8,426 10.49 29 2 7,54111.73 25 3 6,742 13.12 41 4 6,119 14.46 33 5 5,455 16.24 39 6 4,59219.32 30 7 4,425 20.05 26 8 4,083 21.75 54 9 3,782 23.50 100 10 3,38026.35 37 Form III: 1 15,165 5.82 32 2 8,034 11.00 27 3 5,944 14.89 27 45,224 16.96 23 5 5,089 17.41 15 6 4,932 17.97 18 7 4,195 21.16 23 84,029 22.05 35 9 3,520 25.28 100 10 3,181 28.03 16 Form IV: 1 9,732 9.0822 2 6,885 12.85 10 3 6,102 14.50 22 4 5,246 16.89 9 5 4,695 18.89 100 64,344 20.43 20 7 4,088 21.72 12 8 3,615 24.61 67 9 3,258 27.35 17 103,164 28.18 12 Form V: 1 9,466 9.34 14 2 8,166 10.83 15 3 6,807 13.00 204 6,569 13.47 12 5 4,742 18.70 16 6 4,563 19.44 100 7 4,416 20.09 32 84,231 20.98 12 9 3,503 25.41 64 10 3,408 26.13 14 Form VI: 1 9,762 9.0529 2 8,841 10.00 17 3 6,780 13.05 52 4 4,250 20.89 42 5 4,177 21.26 1006 3,888 22.85 37 7 3,846 23.11 20 8 3,766 23.61 41 9 3,724 23.87 17 103,594 24.76 20 Form VII: 1 8,472 10.43 18 2 6,336 13.97 10 3 5,476 16.1710 4 4,893 18.12 9 5 4,664 19.01 100 6 4,236 20.96 30 7 3,676 24.19 10 83,609 24.65 71 9 3,561 24.99 8 10 3,071 29.05 16 Form VIII: 1 7,65611.55 18 2 6,672 13.26 34 3 6,538 13.53 20 4 5,721 15.48 20 5 5,24416.89 54 6 4,700 18.87 25 7 4,475 19.82 45 8 4,330 20.49 34 9 3,74523.74 100 10 3,240 27.50 20 Form IX: 1 7,044 12.56 31 2 6,712 13.18 22 35,487 16.14 40 4 5,218 16.98 30 5 4,897 18.10 46 6 4,714 18.81 42 74,445 19.96 67 8 3,554 25.04 100 9 3,333 26.72 32 10 3,173 28.10 31 FormX: 1 15,817 5.58 31 2 9,123 9.69 23 3 8,280 10.68 27 4 7,953 11.12 28 56,561 13.48 42 6 6,440 13.74 36 7 5,507 16.08 35 8 4,167 21.30 98 94,132 21.49 49 10 3,576 24.88 100 Form XI: 1 10,348 8.54 39 2 7,07712.50 25 3 6,717 13.17 28 4 4,778 18.56 23 5 4,599 19.28 34 6 4,49019.76 100 7 4,239 20.94 51 8 4,186 21.21 18 9 3,504 25.40 66 10 3,39126.26 69 Form XIII: 1 6,579 13.45 85 2 6,121 14.46 63 3 5,424 16.33 28 45,047 17.56 47 5 4,884 18.15 21 6 4,344 20.43 64 7 4,301 20.63 25 84,181 21.24 100 9 3,414 26.08 45 10 3,145 28.36 23 Form XIV: 1 15,0125.88 29 2 7,980 11.08 20 3 5,182 17.10 24 4 4,886 18.14 100 5 4,18921.19 20 6 3,999 22.21 24 7 3,494 25.47 64  8*  9* 10* Form XV: 1 16,4225.38 27 2 9,225 9.58 55 3 8,281 10.68 38 4 6,430 13.76 66 5 5,541 15.9844 6 3,985 22.29 65 7 3,782 23.50 43 8 3,592 24.77 60 9 3,389 26.28 10010 3,358 26.52 30 Form XVI: 1 11,249 7.85 36 2 10,139 8.71 46 3 8,34810.59 100 4 4,555 19.47 31 5 4,201 21.13 51 6 3,955 22.46 50 7 3,74923.72 40 8 3,629 24.51 87 9 3,325 26.79 44 10 2,817 31.74 44 *Furtherpeaks exhibit intensities <3*noise.

1. A method of treating a patient suffering from a depressive disorder,the method comprising administering to the patient an effective amountof1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hemihydrate in crystalline modification VIII (Form VIII),wherein the crystalline modification VIII is characterized by at leastthree characteristic peaks selected from the 2Theta values correspondingto 11.55±0.1, 13.26±0.1, 13.53±0.1, 15.48±0.1, 16.89±0.1, 18.87±0.1,19.82±0.1, 20.49±0.1, 23.74±0.1 and 27.50±0.1 degrees.
 2. The method ofclaim 1, wherein the crystalline modification VIII is characterized bycharacteristic peaks at 2Theta values corresponding to those exhibitedin FIG.
 20. 3. The method of claim 1, wherein the compound isadministered in the form of a pharmaceutical composition comprising aneffective amount of the compound and one or more conventional auxiliarysubstances and/or carriers.
 4. The method of claim 3, wherein thecomposition comprises1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine-hydrochlorideanhydrate in crystalline modification IV (Form IV).
 5. The method ofclaim 3, wherein the composition comprises1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine-hydrochlorideanhydrate in crystalline modification IV (Form IV) and1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine-hydrochloridemonohydrate in crystalline modification V (Form V).
 6. The method ofclaim 1, wherein the depressive disorder is major depressive disorder.7. A method of treating a patient suffering from a depressive disorder,the method comprising administering to the patient an effective amountof1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazinehydrochloride hemihydrate in crystalline modification VIII (Form VIII),wherein the crystalline modification VIII is characterized by an IRspectrum with wavenumbers corresponding to the wavenumbers exhibited inFIG.
 8. 8. The method of claim 7, wherein the compound is administeredin the form of a pharmaceutical composition comprising an effectiveamount of the compound and one or more conventional auxiliary substancesand/or carriers.
 9. The method of claim 8, wherein the compositioncomprises1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine-hydrochlorideanhydrate in crystalline modification IV (Form IV).
 10. The method ofclaim 8, wherein the composition comprises1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine-hydrochlorideanhydrate in crystalline modification IV (Form IV) and1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine-hydrochloridemonohydrate in crystalline modification V (Form V).
 11. The method ofclaim 7, wherein the depressive disorder is major depressive disorder.